A randomized double-blind trial of intranasal dexmedetomidine versus intranasal esketamine for procedural sedation and analgesia in young children

Background Procedural sedation and analgesia are commonly used in the Emergency Departments. Despite this common need, there is still a lack of options for adequate and safe analgesia and sedation in children. The objective of this study was to evaluate whether intranasal dexmedetomidine could provide more effective analgesia and sedation during a procedure than intranasal esketamine. Methods This was a double-blind equally randomized (1:1) superiority trial of 30 children aged 1–3 years presenting to the Emergency Department with a laceration or a burn and requiring procedural sedation and analgesia. Patients were randomized to receive 2.0 mcg/kg intranasal dexmedetomidine or 1.0 mg/kg intranasal esketamine. The primary outcome measure was highest pain (assessed using Face, Legs, Activity, Cry, Consolability scale (FLACC)) during the procedure. Secondary outcomes were sedation depth, parents’ satisfaction, and physician’s assessment. Comparisons were done using Mann–Whitney U test (continuous variables) and Fisher’s test (categorical variables). Results Adequate analgesia and sedation were reached in 28/30 patients. The estimated sample size was not reached due to changes in treatment of minor injuries and logistical reasons. The median (IQR) of highest FLACC was 1 (0–3) with intranasal dexmedetomidine and 5 (2–6.75) with intranasal esketamine, (p-value 0.09). 85.7% of the parents with children treated with intranasal dexmedetomidine were “very satisfied” with the procedure and sedation compared to the 46.2% of those with intranasal esketamine, (p-value 0.1). No severe adverse events were reported during this trial. Conclusions This study was underpowered and did not show any difference between intranasal dexmedetomidine and intranasal esketamine for procedural sedation and analgesia in young children. However, the results support that intranasal dexmedetomidine could provide effective analgesia and sedation during procedures in young children aged 1–3 years with minor injuries. Trial registration: Eudra-CT 2017-00057-40, April 20, 2017. https://eudract.ema.europa.eu/ Supplementary Information The online version contains supplementary material available at 10.1186/s13049-024-01190-5.


Synopsis
Eudra CT nr 2017-000057-40A dex vs ket, version 2 A prospective randomized double-blind study Intranasal dexmedetomidine versus intranasal S-ketamine for children age 1 -3 years for procedural sedation and analgesia in pediatric emergency department.
Injuries are common reasons for a visit to the pediatric emergency department (ED).In the US 24,7% of the pediatric ED visits were injury-related between 2004 and 2008, of which 76,9% were characterized as minor injuries (e.g.fractures, lacerations, burns, contusions, sprains). 1In a Swedish analysis the rate of injury related visits to the ED was 110/1000 person years, of which approximately 60% required active treatment. 2auma often causes pain and anxiety and a visit to the hospital may cause additional anxiety.The therapeutic procedures are usually frightening for children and are often also painful.Pain can be treated with acetaminophen, cox-inhibitors and opioids as well as local anesthetics. 3However the child's fear of further pain or the anxiety concerning the unfamiliar procedure cannot be sufficiently relieved with these analgesics.The absence of good analgosedation (i.e.analgesia and sedation) can result in a very negative experience for both the child and caregivers and may also have impact on any procedures in the future. 4e possibility of performing the necessary procedures required to treat the acute injury in the ED would reduce the need for hospital admissions and as a result reduce overall costs and the use of healthcare resources.More importantly, it is usually more convenient for the children and families to receive the required treatment in the ED when possible so that discharge to their home may be as expedient as possible.
Procedural pain and anxiety have been treated successfully for several years in many pediatric EDs 5,6,7 following the goals and guidelines set for procedural sedation and analgesia (PSA) 8,9 .Commonly intravenous (IV) drugs (e.g.ketamine, propofol, etomidate) are used, ketamine 10 being the most widely reported agent.The safety and adverse effects of ketamine are well reported. 11,12The use of intravenous sedative agents require a sound knowledge of the pharmacological effects of these drugs.
The physician also needs to be able to manage a compromised airway as well as rescue patients from inadvertent deep sedation.In Sweden pediatric EDs are seldom staffed with physicians (i.e.pediatric emergency physicians / emergency physicians) with the necessary skill set, as in those countries where PSA is successfully used.Hence for the benefit of the children, it is needed to identify other medications to reach the same goals that are defined for PSA 8 i.e. adequate and safe analgosedation.
At the ED in Astrid Lindgren Children's hospital (ALB) S-ketamine (oral and intranasal) and nitrous oxide (N2O) are routinely used for PSA.For children between the ages of 1 and 3 years (and weight 10 -15 kg) intranasal (IN) S-Ketamine is used as N2O has been shown to be less effective in younger children.With the dose of S-ketamine that can be used intranasally the effect on analgesia and sedation varies.Therefore, we need to look for other options to be able to perform the necessary procedures effectively and safely.
IN dexmedetomidine has shown promising features for PSA in non-invasive procedures e.g.diagnostic imaging 13 .It has also been used successfully as premedication 14 .Dexmedetomidine is a highly selective α2-adrenoceptor agonist and has both sedative and analgesic effects 15 .It does not cause any local irritation or pain when administered intranasally. 16,17IN dexmedetomidine has a relatively short onset of action, 15 -25 minutes 13,18 .It has no significant effects on respiratory or cardiovascular system when administered intranasally 13,17,18 .These features make dexmedetomidine an interesting drug to study with respect to PSA in the ED. [Date] In this trial we are comparing IN dexmedetomidine with IN S-ketamine to find out if IN dexmedetomidine could offer better circumstances for performing necessary procedures in the emergency department and if it could offer better analgesia and sedation.
Inclusion criteria: Children between 1 and 3 years of age who come to the pediatric ED at ALB with a wound that needs suturing or burn (less than 4% of body surface area).Previously healthy children weighing 10 -15 kg and who are Swedish speaking.Exclusion criteria: Children with ASA  III, current respiratory tract infection, impaired level of consciousness will be excluded from this study.Hypersensitivity for dexmedetomidine or Sketamine.Other contraindications named in the product resume for the trial medicines would categorize the patient as ASA 3 and therefore not suitable for this trial.
Patients are randomized into two groups: 1. intranasal dexmedetomidine, 2. intranasal S-ketamine.This is a double-blind study.Other that the investigational medicine the patient will receive exactly same care as routine in the ALB.During the sedation period patients will be monitored continuously with pulse oximetry and heartrate.
Primary outcome is pain, maximum level of the pain during the procedure compared to the pain level before sedation.Pain will be assessed with FLACC (Facies, Legs, Activity, Cry, Consolability) scale 19 by a trained nurse.The secondary outcome is sedation, patient's/guardian's satisfaction and doctor's opinion about the feasibility of the procedure.Patient/guardian(s) will receive a questionnaire with few questions.Sedation level will be assessed with Ramsay sedation scale 20 .
26 patients in each group (total 52 patients) will give the trial power of 80,7% to yield a statistically significant result.This computation assumes that the mean difference is 2,0 and the common withingroup standard deviation is 2,5 on the FLACC scale.This trial will be started during 2017 as acceptance from Medical Product Agency and Regional Ethical Board Stockholm is received.The trial will is expected to last until 2020.
References please see Supplement 1 [Date]

Informed Consent of Trial Subjects
Information concerning the study is given after doctor's examination and assessment that procedure is necessary and can be performed in the ED.Assessment will be done on medical grounds and according the guidelines.Patient and guardian(s) are given the information about the trial by a doctor (responsible for patient's care / specialist in the ED / primary investigator) for the child on the level he/she understands.Guardian(s) is given a written information (see Supplement 2b).They will be provided necessary time to go through the information and given the opportunity to ask supplementary questions.They will be informed that they at any point have the right to end their child's participation without giving any reason or explanation and without it affecting the necessary treatment.
Guardian(s) is asked to sign a consent (see Supplement 2c) if willing to participate in the trial.As it is a emergency situation both guardians may not be available.The other guardian will be contacted by telephone, information about the study and possibility for questions will be given as for the guardian present.If the guardian not present gives oral consent that will be noted on the consent form and verified with a signature from guardian who is present, as well as by the doctor giving the information about the trial.The guardian who is not present will be asked to sign the consent later.A copy of the consent form will be provided with a prepaid envelope with address.
Patient/guardian will receive a copy of the written information and the signed consent.
Consent will be signed before any procedures related to this trial are done.

Records and reports
Results of the safety and efficacy will be reported to EudraCT database at latest 6 months after the end of the trial.
Declaration of End of Trial Notification will be done within 90 days from termination of the trial.With early termination notification to Medical Product Agency if the reason for termination is trial safety.
In the case of early termination, the sponsor will notify the end of the trial to the Medical Product Agency and the Regional Ethical Board Stockholm immediately and at the latest within 15 days after the trial is halted, clearly explain the reasons, and describe follow-up measures, if any, taken for safety reasons.
For reporting suspected adverse events please see 6.8.3.
A "serious breach" will be reported to Medical Product Agency immediately or latest within seven (7) days.The sponsor is responsible to judge the consequences of the breach and thereby decide whether Medical Product Agency will be informed.
CRF (Supplement 3) and all other essential documents will be archived for 10 years. [Date] 6.2 Background Information

Name and description of the investigational product(s).
Dexmedetomidine is a selective -2 adrenergic agonist with sedative and analgesic properties.It acts by binding to G-protein coupled to -2 adrenergic receptors, which are found in central, peripheral and autonomic nervous systems and also in various vital organs and blood vessels throughout the body.The site of action for sedative effects of dexmedetomidine is locus ceruleus and is mediated by hyperpolarization of noradrenergic neurons thus inhibiting noradrenaline release and inhibiting activity in descending medullospinal noradrenergic pathways. 21bioavailability study of IN dexmedetomidine showed that the pharmacological effects were similar with both routes of administration, but the onset was more rapid after intravenous administration. 16n the same study the elimination half-life was shown to be 114 (107-151) minutes for intranasal administration and 115 (99-145) minutes for intravenous administration.Bioavalability for IN dexmedetomidine was shown to be 63%.Pharmacokinetic data in children is limited.Half-life of dexmedetomidine in children (1 month to 17 years) appears similar to that seen in adults.
S-ketamine is an enantiomer of ketamine.It has mild to good analgesic and sedative properties.
Compared to ketamine its emergence period is remarkably shorter and a more rapid recovery of cerebral functions and less unpleasant psychotomimetic effects are seen with S-ketamine.The reported bioavailability after nasal application ranged from 33% to about 50%.S-ketamine (and ketamine) is approved for intravenous and intramuscular delivery but intranasal use is well documented 22,23,24 and intranasal use in Astrid Lindgren Children's hospital has been routine for many years (see Supplement 4).
The method of administration for both dexmedetomidine and S-ketamine is intravenous according to in the respective SmPC.But ePed (Erfarenhet och evindensbaserad database för barnläkemedel) provide information for intranasal use of these drugs.Please see Supplement 5 and 6.
6.2.2A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.
Initially dexmedetomidine was used for sedation and analgesia in intensive care, but recently its use has been extended to various other clinical situations.In pediatric population it has shown to be successful as premedication and as a sedative for non-invasive procedures i.e. imaging studies.
As premedication 18 and sedative for computed tomography 13 it has been administered intranasally.
IN dexmedetomidine has relatively short onset of action, 15-25 minutes 18 and that makes it a convenient drug for PSA.
Several studies with intravenous 25,26,27,28 and intranasal 13,14,29,30 dexmedetomidine for procedural sedation and premedication have shown the safety of dexmedetomidine.These studies show that dexmedetomidine has minimal effect on cardiorespiratory function.No clinically significant changes on systolic blood pressure, heart rate, respiratory rate or saturation was reported.Clinically significant changes were mostly defined as change of 20% or 2SD below or above normal limits for age or saturation below 95%. [Date] In a study with 62 children (age 2-6 years) comparing intranasal and buccal administration of dexmedetomidine (1,0 g/kg dose) no patient had respiratory depression, bradycardia, or desaturation. 29Another study with 60 patients (children with mean age 17,5  9,5 months (mean weight 10,7  2,8 kg)) intranasal administration of dexmedetomidine (total dose 3,5 g/kg) showed one case of hypoxia and hemodynamic variability in 17%, classified as minor risk. 13Yuen VM et al in their study compared 1,0 and 2,0 g/kg IN dose of dexmedetomidine showed no effect on oxygen saturation levels. 316.2.3 Summary of the known and potential risks and benefits, if any, to human subjects.
For undesirable effects of dexmedetomidine and S-ketamine please see respective product resume (Supplement 7 and 8).As smaller dose is used for sedation than for anesthesia risk for adverse events is smaller.And even though the medications are not administered the way described in product resume there is good evidence of the safety and effectivity of intranasal administration of both dexmedetomidine 13,14,29,30 and S-ketamine 22,23,24 .For further information please see 6.2.2 and 6.2.4 In the product resume for dexmedetomidine common side-effects with IV infusion are hypotension, bradycardia, respiratory depression, nausea, dry mouth, hyper-/hypoglycaemia, agitation.With intranasal administration no significant bradycardia or hypotension has been shown.Nor any other of the above mentioned side-effects have been reported with intranasal administration. 13,14,29,30(please see 6.2.2).
With intranasal administration of S-ketamine no serious adverse events have been reported.The most common complaint has been the bitter taste of the drug. 24 addition to the possible side effects of the medications explained above, pain, distress and discomfort can be caused by the procedure itself.But the procedures are necessary medically and need to be carried through whether or not the patient is included in the study.As is routine today at Astrid Lindgren Children's hospital ED the procedure will be disrupted if effective sedation or analgesia is not achieved.In which case other methods for sedation and analgesia will be used (i.e. that an anesthesiologist can provide deeper sedation and analgesia either in the ED or in the operating theater).
Both medications have minimal circulatory and respiratory effect.The patients are monitored for oxygen saturation and heart rate to be able to detect possible circulatory and respiratory issues.If any aforementioned issues would occur the trained staff in the ED will provide firsthand treatment with supplemental oxygen and ventilation if needed and circulatory support.According to routine anesthesia team will be alarmed.All the equipment for airway and circulatory management will be on hand in the procedure room.

Benefits versus risks of the study
The expected value of this study is to improve knowledge regarding efficacy of intranasal administration of S-ketamine and dexmedetomidine when used for sedation and analgesia during procedural pain for children.It is well known that the effect of different drugs used in this field are less studied regarding use in children.Nevertheless, it is even more important that children can be treated safely with drugs during painful situations.
The route of treatment, inhalation and intranasal application is of special interest for use in the pediatric population since it does not require venous access which is painful itself. [Date] There are studies showing a better safety profile for using S-ketamine and dexmedetomidine intranasally.The incidence of side-effects regarding blood pressure and circulation is lower than for intravenous use why the setup of this study is likely to have less risks than using intravenous injections of sedative and analgetic drugs.
Since these both drugs already are in use in the study hospital in a controlled manner (see Supplements 4, 9) the risk of handling and administration and evaluation is judged to be low and the value of expanding the knowledge of the efficacy of the treatment for painful procedures is stronger than the risk for severe side effects.
The alternative method for sedation and analgesia if intranasal S-ketamine and dexmedetomidine are not potent enough for the procedure is more profound anaesthesia which is also potentially more riskful and requires more resources.
In conclusion, the benefit-risk assessment of both drugs used in this study is considered to be positive in the population in question.Both drugs used in this study are considered to give pain alleviation and sedation.And both drugs have been shown to have a good safety profile in several studies as well as in routine clinical use in the study hospital.

Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).
Intranasal administration is an easy and convenient way of administrating a medicine. 32It does not require intravenous access, and applying an intravenous access is often frightening for a child.Dexmedetomidine is odorless and tasteless, and can be administered intranasally without discomfort.Which makes it easy to use in the pediatric population.The highly vascularized nasal mucosa and the olfactory tissue in direct contact with the central nervous system allow nasally administered drugs to be rapidly transported into the bloodstream and brain, with onsets of action approaching that of intravenous therapy.First-pass metabolism via the liver is also avoided and that results in high bioavailability of many medications. 33 atomizer has been shown to deliver a consistent volume of the drug and it has shown to increase patient acceptance compared to nasal drops.The administration method did not affect the efficacy of the drug. 34We have chosen to use an atomizer to administer intranasal drugs because it is well accepted and recommended in ePeds database instructions (see Supplement 5 and 6) The dose 2,0 micrograms/kg will be used and this is chosen after the current practice for premedication in Astrid Lindgren Children's hospital (please Supplement 9) and this dose for procedures is recommended even in ePed database (see Supplement 5) This dose has also been shown to provide safe and efficient sedation. 31 Dexdor 100 microg/ml concentration is used without further dilution.A 1 ml syringe with a special soft plug for nasal administration (MAD Nasal) will be used.The volume should not exceed 0,2 ml per nostril.In this patient group 10 -15 kg dose will be 20 -30 g which in volume means 0,2 -0,3 ml.This means a maximum of one spraying per nostril.
S-Ketamine 25 mg/ml concentration is used without further dilution.A 1 ml syringe with a special soft plug for nasal administration (MAD Nasal) will be used.S-Ketamine 25 mg/ml.Dose 1,0 mg/kg.Children 10 -15 kg, dose 10 -15 mg which gives volume 0,4 -0,6 ml.Maximum [Date] recommended volume for S-ketamine is 0,3 ml / nostril. 35IN S-ketamine has been used at ALB for many years for PSA (see Supplement 4).Dosage follows the instructions in the ePeds database (see Supplement 6) There will be only one treatment occasion.Patient will receive one dose of the medicine for the planned procedure which will be done during the emergency department visit.
6.2.5 A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).
This study will be conducted according to the protocol and current regulations LVFS 2011:19, ICH GCP and the latest version of Helsinki declaration.

Description of the population to be studied.
Children at the age of 1 -3 years who present to the emergency department with a laceration in need of suturing or burn less than 4% of body surface area.Previously healthy Swedish speaking patients.

6.2.7
References to literature and data that are relevant to the trial, and that provide background for the trial.
Please see Supplement 1.

Trial Objectives and Purpose
The overall aim is to identify other possibilities for non-invasive, safe and efficient procedural analgesia and sedation to be used for children in the emergency department.
The objective of this study is to evaluate whether intranasal dexmedetomidine can provide better, faster onset of action and more effective, analgesia and sedation during procedure than intranasal Sketamine among children between 1 and 3 years of age with minor injuries with respect to analgesia measured by FLACC in a prospective randomized double-blind study.
We are hoping that the results from this study can be used for new recommendations about using dexmedetomidine for PSA for painful procedures in combination with local anesthetics in the patient group mentioned above. [Date] 6.4 Trial Design 6.4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.
Primary outcome is pain measurement during the procedure, pain during the procedure compared to the pain right before procedure start.Pain will be assessed by trained ED nurses with FLACC (Face, Legs, Activity, Cry, Consolability) scale 19 and change of 2 points on the scale of 0-10 is considered as significant change.For closer explanation of the behavioral components of this scale please see Supplement 10.
FLACC was initially validated by Merkel and colleagues with children age 2 mo -7 yr postoperatively. 19Since then it has been tested and validated in several settings (e.g.postoperatively, PICU, trauma unit and oncology unit) 36 .A translation to Swedish and validation of the Swedish version was done by Nilsson et al. 37 This study also concluded that FLACC can reliably be used for assessing procedural pain, this study was carried through with children aged 5 -16 years.There are several studies on procedural sedation that have used FLACC scale as pain assessment scale.As FLACC was initially validated for children from 2 months of age and its reliability in procedural sedation also is shown we have chosen this pain scale for the assessment tool in our study.
Secondary outcome is sedation score during the procedure with the baseline defined as score before administration of medicine.Other secondary outcomes are patient's/guardian's satisfaction and doctor's opinion about the feasibility of the procedure.Patient/guardian(s) will receive a questionnaire with few questions.Doctor's opinion will be recorded on the CRF.
To assess the sedation Ramsay sedation scale 20 will be used.A change of 1 point on the scale of 1-6 is considered as significant change.For closer explanation of the components of this scale please see Supplement 11.Ramsay scale is translated to Swedish by SFAI (Svensk förening för anestesi och intensivvård).
The Ramsay sedation scale was first published 1974 20 and today it is one of the most widely used tools for observationally based sedation assessment.Ramsay sedation score is not validated for children, but it is widely used sedation scale for children and has also been used in many studies for intranasal dexmedetomidine 13,31,38 .

A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
A prospective, randomized double-blind clinical trial.
Patients will be randomized into two groups; group 1 intranasal dexmedetomidine, group 2 intranasal S-ketamine.56 patients will be enrolled in the trial, 26 in each group.

Paracetamol
• All patients will receive oral paracetamol 40 mg/kg (max 2 g) on the arrival to the ED or at least 1-1,5 hours before procedure.This is a routine treatment of pain for all patients with injuries in the ED at ALB.
2. Doctor's examination and assessment that procedure is necessary and can be performed in the ED.Assessment will be done on medical grounds and according the guidelines.
[Date] 4. Information about the trial • Information will be provided by treating physician / specialist Dr in the ED / primary investigator • Spoken and written information will be provided (please see Supplement 2b)

Written consent
• Please see page 8 in the protocol • Please see Supplement 2b

Randomization
• The patients will be randomized in a double fashion to minimize bias.
• Randomization will be done by a person not participating the trial.Name of medicine will be written on a paper and put in an envelope which will be sealed and numbered.Patient will choose the envelop from those that are left.• The closed envelope will be given to the nurse who draws up the trial medicine.

ECG
• Assessed by the investigator in charge to exclude AV block II/III.
8. Administration of trial medicine by a blinded nurse (different from who drew up the trial drug) • intranasal dexmedetomidine (Dexdor 100microg/ml) 2,0 microg/kg or • intranasal S-ketamine (Ketanest 25mg/ml) 1,0 mg/kg 9. Monitoring and observation • continuous SpO2 and heartrate o beginning from the administration of trial medicine o until sedation score 1 according to Ramsay is reached again [Date] • Pain (FLACC) and Sedation (Ramsay) assessment o at 0 -5 -10 min from administration of study medicine and continue every 5 minutes until Ramsay score 2 is reached o at the start of the procedure and every 5min under the procedure o after procedure every 10 minutes until the patient has recovered and reached Ramsay score 1 10.Procedures will be will be carried out according the normal routines Burn 1. Gauze soaked with buffered lidocaine (10ml Xylocain 10mg/ml + 2ml NaHCO3) will be put on top of the burn area (maximum lidocaine dose 5mg/kg) -at the same time/right after IN medication is administered -for 20 -30 minutes 2. Cleaning and dressing of the burn as per routine protocol -as sedation score 2 on Ramsay sedation scale is reached or 30 minutes from administration of intranasal medicine Wounds 1. Local anesthesia with buffered lidocaine (10ml Xylocain 10mg/ml + 2ml NaHCO3) is infiltrated on the wound with needle and syringe maximum dose lidocaine without adrenalin 5mg/kg maximum dose lidocaine with adrenalin 7mg/kg -as sedation score 2 on Ramsay sedation scale is reached or 30 minutes from administration of intranasal medicine 2. Suturing of the wound as per routine protocol -5 minutes after application of local anesthesia 11.Patient will be able to leave the emergency department when Ramsay score 1 is reached and he/she has returned to his/hers habitual condition.And as the management of the injury is completed according the normal routine and further information and possible follow-ups are given.

A description of the measures taken to minimize/avoid bias, including:
(a) Randomization.
The patients will be randomized in a double fashion to minimize bias.Randomization will be done by a person not participating the trial.Randomization will be done in blocks of 10 subjects (5 from both arms), except one block with 12 subjects.A list for randomization will be created after a random draw up.Envelopes will be filled with information according to randomization list and numbered.Envelopes will then be used in number order.

A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
Paracetamol 40 mg/kg orally (oral suspension), max 2 g.Dose 40 mg/kg is used for pain management as loading dose according to clinical routine at Astrid Lindgren Children's hospital (see Supplement 4 page 30) which is based on the Swedish national guidelines 35 . [Date] Buffered lidocaine (10ml Xylocain 10mg/ml + 2ml NaHCO3) is used for local anesthesia.Maximum dose of lidocaine without adrenalin is 5mg/kg and with adrenalin is 7mg/kg (see Supplement 4 page 29) Intranasal dexmedetomidine 2,0 micrograms/kg as one dose.Dexdor 100 microg/ml concentration is used without further dilution.A 1 ml syringe with a special soft plug for nasal administration (MAD Nasal) will be used.
Intranasal S-ketamine 1,0 mg/kg as one dose.Ketanest 25mg/ml concentration is used without further dilution.A 1 ml syringe with a special soft plug for nasal administration (MAD Nasal) will be used.
A contract with the hospital pharmacy will be made for labelling and packaging the investigational products.The commercial products of dexmedetomidine (Dexdor 100 g/ml) and S-ketamine (Ketanest 25mg/ml) will be used.The labelling will include study number, responsible investigator and statement "for clinical testing only".As well information about the drug: name, batch number, expiry date.

The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
The whole process from administration of the drug and finish of the procedure will take about 30-60 minutes.In addition to that a recovery time up to one hour can be expected.
No further follow-ups are necessary, except the follow-up required for the injury and that will follow the normal guidelines.

A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial and entire trial.
The procedure will be stopped if it cannot be carried through because of insufficient pain relief judged by doctor, patient or guardian.As well as if any adverse events (e.g.breathing problems, desaturation, vomiting) occur.Furthermore, if patient/guardian decides not to continue the procedure.
Eventually if administration of the trial medicine must be stopped because of local irritation, but that will only be the case when the dose needs to be divided into both nostrils as nasal administration only takes 1-2 seconds.

Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
Marketed drugs will be used.Placebo cannot be used since the procedure is painful and cannot be carried out without an adequate treatment.Both drugs are used in clinical practise (please see Supplements 4-6, 9).Dexmedetomidine (Dexdor 100g/ml) and S-ketamine (Ketanest 25mg/ml) will be ordered from the hospital pharmacy with the labelling presented in section 6.4.4. [Date]

Maintenance of trial treatment randomization codes and procedures for breaking codes.
Envelopes for randomization codes will be kept safely (locked in) in the ED as well a sealed envelope for breaking codes to be used if patient presents with adverse reactions.
6.4.9The identification of any data to be recorded directly on the CRFs (i.e.no prior written or electronic record of data), and to be considered to be source data.
Please see the CRF attached (Supplement 3).

Subject inclusion criteria.
• 1 -3 years of age • A laceration in need of suturing or burn less than 4% of body surface area • Weight 10 -15 kg • Previously healthy • Swedish speaking 6.5.2Subject exclusion criteria.
• ASA classification ≥ III (see Supplement 12) • Current respiratory tract infection • Impaired level of consciousness • Hypersensitivity for dexmedetomidine or S-ketamine.
• Further contraindications named in the product resume for the trial medicines would categorize the patient as ASA III and therefore not suitable for this trial.o Advanced heart block (grade 2 or 3) unless paced ▪ ECG to exclude AV block II/III o Known and untreated uncontrolled hypotension ▪ Bloodpressure is not to be measured on patients with no history o acute cerebrovascular conditions (=patient with any acute neurologic symptoms)

Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying:
(a) When and how to withdraw subjects from the trial/ investigational product treatment.
Patients will not be included in the study if they do not meet inclusion criteria or meet any of the exclusion criteria.The study includes only one treatment occasion.Patient/guardian can at any time choose to stop participation in this trial and will then be treated according to the normal routines of the hospital. [Date] (b) The type and timing of the data to be collected for withdrawn subjects.
CRF will be used for collecting data and data will be registered until subject withdraws.The reason for withdrawal will be registered if patient is willing to provide one.
(c) Whether and how subjects are to be replaced.
Withdrawn subjects will be replaced so that planned number of subjects (52=26/group) is reached The follow-up for subjects withdrawn from investigational product treatment/trial treatment.
Patient will be treated as per normal routines if trial needs to be discontinued.If any adverse events occur patient will be treated and followed up according to the need and type of side effect.All adverse events will be recorded and reported to Medical Product Agency.

Treatment of Subjects
6.6.1 The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.
Paracetamol 40 mg/kg orally (oral suspension) (maximum dose 2 g) on arrival to the Emergency Department or at least 1-1,5 hours before procedure.
Buffered lidocaine (10ml Xylocain 10mg/ml + 2ml NaHCO3) is used for local anesthesia.Maximum dose of lidocaine without adrenalin is 5 mg/kg and with adrenalin is 7 mg/kg Buffered lidocaine will be injected locally on the wound when Ramsay score 2 is reached and 5 minutes prior procedure.With burns a gauze soaked in buffered lidocaine will be put on the burn 20 -30 min before the procedure.
Dexmedetomidine 2,0 microg/kg intranasally, one dose.Dexdor 100 microg/ml concentration is used without further dilution.A 1 ml syringe with a special soft plug for nasal administration (MAD Nasal) will be used.
Monitoring with SpO2 and pulse until Ramsay scale 1 after the procedure is reached and child has returned to his/her normal behavior.

S-ketamine
1,0 mg/kg intranasally, one dose.Ketanest 25mg/ml concentration is used without further dilution.A 1 ml syringe with a special soft plug for nasal administration (MAD Nasal) will be used.
Monitoring with SpO2 and pulse until Ramsay scale 1 is reached and child has returned to his/her normal behavior. [Date] 6.6.2Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
2 hours must have passed from administration of other sedatives or opioids.
No rescue medicine will be used.If effective analgesia and sedation is not reached the procedure will be stopped and other methods to perform the necessary treatment will be used (please see 6.2.3) 6.6.3Procedures for monitoring subject compliance.
Not needed in this trial.

Assessment of Efficacy
6.7.1 Specification of the efficacy parameters.
FLACC and Ramsay are the efficacy parameters used in this trial.
To assess the effectivity on pain management during the procedure FLACC (Face, Legs, Activity, Cry, Consolability) scale will be used.
The sedation effectivity of the drugs used will be assessed with Ramsay sedation scale.
For further information on FLACC scale and Ramsay sedation scale please see 6.4.1.

Methods and timing for assessing, recording, and analysing of efficacy parameters.
Timing for assessment please see 6.4.2.Data will be recorded on CRF, please see Supplement 3.

Assessment of Safety
6.8.1 Specification of safety parameters.
Adverse event (defined in Article 2(m) of Directive 2001/20/EC) Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
Adverse reaction (defined in Article 2(n) of Directive 2001/20/EC) All untoward and unintended responses to an investigational medicinal product related to any dose administered.
Serious adverse event or serious adverse reaction (defined in Article 2(n) of Directive 2001/20/EC) Any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect; Unexpected adverse reaction (defined in Article 2(p) of Directive 2001/20/EC) An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.investigator's brochure for an unauthorized investigational product or summary of product characteristics for an authorized product) [Date] Suspected unexpected serious adverse reaction (SUSAR) An untoward and unintended response to a study drug, which is not listed is the applicable product information, and meets one of the following serious criteria: results in death, is life-threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect Adverse events and reactions will be classified as serious if it results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity.

Metabolism och nutrition
All suspected unexpected serious adverse events that are deadly or life-threatening will be reported by the sponsor (Malin Rydh-Rinder) to Medical Products Agency and Ethical Review Board Stockholm within seven (7) days and complementary information within eight (8) days after the preliminary report.All other suspected unexpected serious adverse events will be reported within fifteen (15) days.
In addition to above mentioned a yearly report about adverse events will be filed to Medical Products Agency and Ethical Review board Stockholm as long as the clinical trial is active.
A "serious breach" is a violation or deviation of the protocol which is likely to effect to a significant degree the safety or integrity of the subjects of the trial; or the scientific value of the trial.A "serious breach" will be reported to Medical Product Agency immediately or latest within seven (7) days.The sponsor is responsible to judge the consequences of the breach and thereby decide whether Medical Product Agency will be informed.

6.8.4
The type and duration of the follow-up of subjects after adverse events.
Patients with suspected adverse effects will be monitored at the emergency department.The duration of the observation will depend on the type and duration of the adverse event and if necessary patient will be admitted for further monitoring.
6.9 Statistics 6.9.1 A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).
Comparison between treatment groups will be performed using t-test, no interim analysis is planned.The study is intention to treat.Comparisons will be performed on group level between those eligible and those included in the trial.
6.9.2The number of subjects planned to be enrolled.In multicentre trials, the numbers of enrolled subjects projected for each trial site should be specified.Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
The criterion for significance (alpha) has been set at 0,050.The test is 2-tailed, which means that an effect in either direction will be interpreted.
With the proposed sample size of 26 and 26 (total 52) for the two groups, the study will have power of 80,7% to yield a statistically significant result.This computation assumes that the mean difference is 2,0 and the common within-group standard deviation is 2,5.This effect was selected as the smallest effect, measured with FLACC, that would be important to detect, in the sense that any smaller effect would not be of clinical or substantive significance.It is also assumed that this effect size is reasonable, in the sense that an effect of this magnitude could be anticipated in this field of research.
6.9.3The level of significance to be used.
Please see 6.9.2 [Date] 6.9.4 Criteria for the termination of the trial.
The trial will be completed at the last visit of the last subject.
If several serious adverse occur, patients are difficult to enrol or the time to reach the planned number of subjects is prolonged the trial will be terminated earlier than planned.
As the investigational medicine is administered only once there is no need for further treatment or follow-up.
In the case of early termination, the sponsor will notify the end of the trial to the Medical Product Agency and the Reginal Ethical Board Stockholm immediately and at the latest within 15 days after the trial is halted, clearly explain the reasons, and describe follow-up measures, if any, taken for safety reasons.
6.9.5 Procedure for accounting for missing, unused, and spurious data.
Missing data will be excluded from statistical calculations on group level.Patients with missing data will be discussed separately in the results section.
6.9.6 Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final report, as appropriate).
Any non-substantial deviations from original protocol will be recorded.Substantial deviations will be reported according to Communication from the European Comission CT-1 2010/C82/01.Amendments to the trial are regarded as substantial when they are likely to have a significant impact on: the safety or physical or mental integrity of the clinical trial participants, or the scientific value of the trial.The sponsor will assess whether an amendment is to be regarded as substantial.Substantial amendments will be reported to Medical Product Agency and/or to Regional Ethical Board Stockholm depending on the amendment.Decision on which authority (or both) will be notified will be assessed and decided by the instructions given in CT-1 2010/C82/01, 3.5 and LVFS2011:19,7.
If patient safety is endangered the trial will discontinued and this will reported to the Medical Product Agency authorities.
Deviation, if any, will be stated in the final report.
6.9.7 The selection of subjects to be included in the analyses (e.g.all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects).
Patients that meet inclusion criteria and are willing to participate in the study are randomized.All randomized patients who have received investigational medicine or the comparator and gone through the procedure will be included in the analysis.